One aim of radiation therapy is to deliver a prescribed dose of radiation to a target volume while minimizing the dose to surrounding healthy tissues. The extent to which this can be accomplished depends on many factors including the beam dosimetric characteristics and the delivery method. The use of proton beams provides the possibility of superior dose conformity to the treatment target as well as a better normal tissue sparing as a result of the Bragg peak effect (Wilson, R. R., “Radiological uses of fast protons”, Radiology, 1946, 487-495). While photons show high entrance dose and slow attenuation with depth, protons have a very sharp peak of energy deposition as a function of beam penetration. As a consequence, it is possible for a larger portion of the incident proton energy to be deposited within or very near a three-dimensional (“3D”) planning target volume (“PTV”), thus avoiding radiation-induced injury to surrounding normal tissues.
Despite the dosimetric superiority characterized by the sharp Bragg peak, utilization of proton therapy has lagged behind that of photon therapy. For example, the operating regime (the total operating cost for accelerator maintenance, energy consumption, and technical support) for proton accelerators is at least an order of magnitude higher than electron/X-ray medical accelerators. Currently, proton therapy centers utilize cyclotrons and synchrotrons (Jongen, A. A., “Proton therapy system for MGH's NPTC: equipment description and progress report”, Cyclotrons and their Applications, ed J. C. Cornell (New Jersey: World Scientific), 1996, pp. 606-609; Cole, F. T. “Accelerator Considerations in the Design of a Proton Therapy Facility”, Particle Acceleration Corp. Rep., 1991). Despite a somewhat limited number of clinical cases from these facilities, treatment records have shown encouraging results particularly for well localized radio-resistant lesions (Fuss, M., et al., “Proton radiation therapy (PRT) for pediatric optic pathway gliomas: Comparison with 3D planned conventional photons and a standard photon technique”, Int. J. Radiation Oncology Biol. Phys., 1999, 1117-1126; Slater, J., et al., “Conformal proton therapy for prostate carcinoma”, Int. J. Radiation Oncology Biol. Phys., 1998, 299-304; Shipley, W., et al., “Advanced prostate cancer: the results of a randomized comparative trial of high dose irradiation boosting with conformal protons compared with conventional dose irradiation using photons alone”, Int. J Radiation Oncology Biol. Phys., 1995, 3-12; Kjellberg, R. N., Stereotactic Bragg Peak Proton Radiosurgery for Cerebral Arteriovenous Malformations Ann Clin. Res. Supp. 47, 1986, 17-25). However, the availability of proton radiation therapy needs to be greatly improved. Making available a compact, flexible, and cost effective proton therapy system would enable the widespread use of this superior beam modality and therefore bring significant advances in the management of cancer.
For a long time proton therapy has led the way in delivering precise, conformal radiation therapy and in many comparative studies has shown improved localization of dose as compared to conventional photon techniques (Archambeau, J. O., et al., 1992, “Role of proton beam irradiation in treatment of pediatric CNS malignancies”, Int. J. Radiation Oncology Biol. Phys. 287-94; Slater, J. D., et al., “The potential for proton beam therapy in locally advanced carcinoma of the cervix”, Int. J Radiation Oncology Biol. Phys., 1992, 343-47; Slater, J. M., et al., “Carcinoma of the tonsillar region: potential for use of proton beam therapy”, Int. J. Radiation Oncology Biol. Phys., 1992, 311 -19; Tatsuzaki, H., et al., “Comparative treatment planning: proton vs x-ray beams against glioblastoma multiform”, Int. J. Radiation Oncology Biol. Phys., 1991 265-73, “Tatsuzaki 1991a”; Tatsuzaki, H., et al. “3-d comparative study of proton vs. x-ray radiation therapy for rectal cancer”, Int. J. Radiation Oncology Biol. Phys., 1991, 369-74, “Tatsuzaki 1991b; Lee, M., et al., “A comparison of proton and megavoltage x-ray treatment planning for prostate cancer”, Radiother. Oncol., 1994, 239-53; Miralbell, R., et al. “Potential reduction of the incidence of radiation-induced second cancers by using proton beams in the treatment of pediatric tumors”, Int. J. Rad. Onc. Biol. Phys., 2002, 824-829). In recent years, the planning and delivery of x-rays has improved considerably so that the gap between conventional proton techniques (superposition of proton fields with uniform planar fluence) and x-ray methods has significantly decreased. The main pathway of research has been toward the optimization of individual beamlets and the calculation of optimal intensity distributions (for each beamlet) for intensity modulated treatments. Lomax, A. J., et al. (“A treatment planning inter-comparison of proton and intensity modulated photon radiotherapy”, Radiother. Oncol., 1999, 257-71, “Lomax 1999a”) performed comparative studies between standard photon, intensity-modulated photon and proton plans as applied to different lesion sites and found that for the majority of cases proton plans (with 2-3 field arrangements) provided an advantage by reducing both the mean dose and V50 (volume of the structure irradiated to 50% of the target dose) for all organs at risk stemming from the advantageous physical characteristics of protons. On the other hand, there was an example of acinus cell carcinoma in which the target volume was relatively large (350 cc) and partially wrapped around the brain stem. The results of this case demonstrated that intensity modulated (IM) photon plan yielded superior sparing of the brain stem at almost all dose levels. The advantage of IM photons over conventional protons for this particular case does not seem to emanate from the difference in dosimetric characteristics between both modalities. Instead, this advantage seems to be related to the advantage of inverse planning methods over the forward planning methods used for the proton plans in this study. The implementation of the inverse planning techniques into proton therapy has somewhat lagged behind those for photon beam modality. This was apparently due to the limitations in the initial design of the beam delivery methods in conventional proton accelerators. With the advent of three-dimensional spot scanning technique, the implementation of intensity modulation for conventional proton accelerators has been enabled. Recent clinical findings (Lomax, A. J., “Potential role of intensity-modulated photons and protons in the treatment of the breast and regional nodes”, Int. J Rad. Oncol. Biol. Phys., 2003, 785-792, “Lomax et al. 2003a”; Lomax, A. J., et al., “Intensity modulation in radiotherapy: photons versus protons in the paranasal sinus”, Radiother. Oncol., 2003, 11-18, “Lomax et al. 2003b”) suggest that the employment of optimization methods into proton therapy will further improve dose distribution within the target and sparing of the critical structures as compared to IM photons.
Intensity modulation applied to conventional photon beams implies the modulation of its intensity in the plane perpendicular to the beam's propagation direction. This suggests that there is no control over the photon depth dose distribution, preset by the energy spectrum of photons coming out of the accelerator's head. Unlike photons, the depth dose distribution for proton beams can be modulated in such a way as to give SOBP along the target's depth dimension. This is used in conventional proton beam delivery methods in which range shifters are implemented to modulate initially monoenergetic proton beam to give SOBP (Moyers, M., “Proton therapy”, The Modern Technology of Radiation Oncology, ed J Van Dyk, Medical Physics Publishing, Madison, 1999). In conventional proton beam delivery systems the modulation of the Bragg peak intensity is such that the depth-dose distribution for any single field is flat, with multiple field plans calculated by the simple weighted addition of homogeneous single field dose distributions (Lomax. A. J., et al. “3D treatment planning for conformal proton therapy by spot scanning Proc. 19th L H Gray Conference, ed Faulkner, K., et al., (London: BIR publishing), 1999, pp. 67-71, “Lomax 1999b”). This differs from intensity modulation for photons, where a number of individually inhomogeneous fields are used in such a way as to achieve a homogeneous dose distribution within the target, simultaneously reducing the dose to the normal tissues/critical structures. In 1999, Lomax earlier defined a 2.5D intensity modulation method (Lomax, A., “Intensity modulation methods for proton radiotherapy”, Phys. Med. Biol., 1999, 185-205, “Lomax 1999c”). The full 3D delivery method described by Brahme et al. (“Optimization of proton and heavy ion therapy using an adaptive inversion algorithm” Radiother. Oncol. 1989, 189-197), and more recently by Carlsson et al. (“Monte Carlo and analytical calculation of proton pencil beams for computerized treatment plan optimization”, Phys. Med. Biol., 1997, 1033-53) exploits the 3D localization of dose in the Bragg peak by intensity modulating individual narrow beam Bragg peaks in three dimensions.
Laser acceleration was first suggested in 1979 for electrons (Tajima, T., et al., “Laser electron accelerator”, Phys. Rev Lett., 1979, 267-270) and rapid progress in laser-electron acceleration began in the 90's after chirped pulse amplification (“CPA”) was invented (Strickland, D., et al., “Compression of amplified chirped optical pulses”, Opt. Comm., 1985, 219-221) and convenient high fluence solid-state laser materials such as Ti:sapphire were discovered and developed. The first experiment that has observed protons generated with energies much beyond several MeV (58 MeV) is based on the petawatt Laser at Lawrence Livermore National Laboratory (Key, M. H., et al. “Studies of the Relativistic Electron Source and related Phenomena in Petawatt Laser Matter Interactions”, First International Conference on Inertial Fusion Sciences and Applications, 1999; Snavely, R. A., et al. “Intense high energy proton beams from Petawatt Laser irradiation of solids”, Phys. Rev. Lett., 2000, 2945-2948). Until then there had been several experiments that observed protons of energies up to I or 2 MeV (Maksimchuk, A., et al., “Forward Ion acceleration in thin films driven by a high intensity laser”, Phys. Rev. Lett., 2000, 4108-4111). Another experiment at the Rutherford-Appleton Laboratory in the U.K. has been reported recently with proton energies of up to 30 MeV (Clark, E. L., et al., “Energetic heavy ion and proton generation from ultraintense laser-plasma interactions with solids”, Phys. Rev. Lett., 2000, 1654-1657). The mechanism for proton acceleration is well studied. It has long been understood that ion acceleration in laser-produced plasma relates to the hot electrons (Gitomer, S. J., et al., “Fast ions and hot electrons in the laser-plasma interaction” Phys. Fluids, 1986, 2679-2686). A laser pulse interacting with the high-density hydrogen-rich material (plastic, water vapor on the surface of the metal foil) ionizes it and subsequently interacts with the created plasma (collection of free electrons and ions). The commonly recognized effect responsible for ion acceleration is charge separation in the plasma due to high-energy electrons, driven by the laser inside the foil (Maksimchuk et al. 2000; Yu, W. et al., “Electron acceleration by a short relativistic laser pulse at the front of solid targets”, Phys. Rev. Lett., 2000, 85, 570-573) or/and an inductive electric field as a result of the self-generated magnetic field (Sentoku, Y., et al., “Bursts of Superreflected Laser Light from Inhomogeneous Plasmas due to the Generation of Relativistic Solitary Waves”, Phys. Rev. Lett., 2000, 3434-3437), although a direct laser-ion interaction has been discussed for extremely high laser intensities ˜1022 W/cm 2 (Bulanov, S. V., et al., “Generation of Collimated Beams of Relativistic Ions in Laser-Plasma Interactions”, JETP Letters, 2000, 407-411).
Using numerical simulations (Fourkal, E., et al., “Particle in cell simulation of laser-accelerated proton beams for radiation therapy”, Med. Phys., 2002, 2788-98), the laser/foil parameter range was investigated that can lead to effective proton acceleration. It was found that thin foils (0.5-1 microns thick) with electron densities of nc=5×1022 cm−3 and laser pulse intensity I=1021 W/cm2 and length L=50 femtosecond are amenable to effective proton acceleration capable of producing protons with energies 200 MeV and higher. In the previous experimental investigations the thickness of foils was tens and sometimes hundreds of microns with laser pulse lengths of several hundred femtoseconds, leading to lower proton energies. Maximizing the proton energy by irradiating thin foils (less than 1 micrometer thick) with ultrashort high-intensity lasers is an area currently under development.
Simulations of the laser acceleration of protons have been reported in Fourkal et al. (2002). It was shown that due to the broad energy spectrum of the accelerated protons, it is very difficult to use laser-accelerated protons for therapeutic treatments without prior proton energy selection. Once energy selection is achieved, it is possible to give a homogeneous dose distribution through the so-called spread out Bragg's peak (SOBP). The particle selection system capable of yielding protons with a required energy spectrum and intensity has been studied by Fourkal et al. (2003).
The inventions provided herein can be used with the compact, flexible and cost-effective laser-accelerated proton therapy systems as described in (Fourkal et al. 2002; Fourkal, E., et al., “Particle selection for laser-accelerated proton therapy feasibility study”, Med. Phys., 2003, 1660-70; Ma, C.-M, et al. “Laser Accelerated proton beams for radiation therapy”, Med. Phys., 2001, 1236). These systems are based upon several technological developments: (1) laser-acceleration of high-energy protons, and (2) compact system design for particle (and energy) selection and beam collimation. Related systems, devices, and methods are disclosed in International Patent Application No. PCT/US2004/017081, “High Energy Polyenergetic Ion Selection Systems, Ion Beam Therapy Systems, and Ion Beam Treatment Centers”, filed on Jun. 02, 2004, the entirety of which is incorporated by reference herein. For example, FIG. 17 of the PCT/US2004/017081 application (and reproduced herein as FIG. 1a) depicts a laser-accelerated polyenergetic positive ion beam therapy system, further details of which can be found in that application. Likewise, FIG. 41 of the PCTIUS2004/017081 application (and reproduced herein as FIG. 1b) depicts a sectional view of a laser-accelerated high energy polyenergetic positive ion therapy system, further details of which can be found in that application. Such systems provide a way for generating small beamlets of polyenergetic protons, which can be used for irradiating a targeted region (e.g., tumors, lesions and other diseased sites) to treat patients.
Treatment strategies have also been described, for example FIG. 43 of the PCT/US2004/017081 application (and reproduced herein as FIG. 1c) depicts a flow chart of a method of treating a patient using polyenergetic high energy positive ions, further details of which can be found in that application. The disclosed treatment strategies include determining dose distributions of a plurality of therapeutically suitable high energy polyenergetic positive ion beams for irradiating a targeted region and delivering a plurality of therapeutically suitable high energy polyenergetic positive ion beams (i.e., beamlets) to the targeted region. Although determining dose distributions are provided in the PCT/US2004/017081 application, further improvements are needed in optimizing beamlet treatment plans that maximize radiation to targeted regions while minimizing radiation to surrounding critical organs, tissues and structures. Accordingly, one aspect of the present invention provides methods for optimizing polyenergetic proton beamlet treatment plans that maximize polyenergetic proton radiation to targeted regions while minimizing radiation to surrounding critical organs, tissues and structures.